7th proceedings indiana conference

George K. Stookey EditorProceedings of the 7th Indiana Conference Indianapolis, Indiana

Clinical Models Workshop: Remin-Demin, Precavitation, Caries

George K. Stookey Indiana University School of Dentistry Therametric Technologies, Inc. 351 W. 10th Street, Suite 222 Indianapolis, IN 46202-4119 U.S.A.

Library of Congress Cataloging-in-Publication Data Library of Congress Control Number: 2006908914 Clinical models workshop: Remin-demin, precavitation, caries: proceedings of the 7th Indiana Conference initiated by Indiana University School of Dentistry, Indianapolis, Indiana; supported by the National Institute of Dental and Craniofacial Research (Grant Number 1 R43 DE016767 and the Task Force for Design and Analysis in Dental and Oral Research; and held at the Indianapolis Marriott Downtown, Indianapolis, July 3-5, 2005. George K. Stookey, editor. Includes bibliographic references. ISBN 0-9655149-5-1 2005 Indiana University School of Dentistry All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Therametric Technologies, Indiana University Emerging Technologies Center, 351 West Tenth Street, Indianapolis, IN 46202-4119, USA), except for brief excerpts in connection with reviews of scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The publisher, editors, and sponsor cannot assume any legal responsibility for information on instrumentation or on drug dosage and administration contained in this publication. The respective user must check its accuracy by consulting other sources of reference in each individual case. The use of general descriptive names, registered names, trademarks, etc., in this publication, even if not identified as such, does not imply that they are exempt from the relevant protective laws and regulations or free for general use. Cover design by Mark. A. Dirlam. Interior design by Linda Levandoski, Shawna Ros, Dorothy Lyon, Scott Bennett, Robin Holtel and Evie Groll. Camera-ready copy prepared by Karen E. Wilczewski, Marketing Communications Consultants. Printed and bound by Printing Partners. Printed in the United States of America. ISBN 0-9655149-5-1

AcknowledgmentThe Editor gratefully acknowledges the National Institute of Dental and Craniofacial Research (Grant Number 1 R43 DE016767 and the Task Force for Design and Analysis in Dental and Oral Research for sponsoring the 7th Indiana Conference, and for sharing our commitment to uphold the highest standards and ideals in the pursuit of knowledge. A special word of thanks go to Theresa J. Norris, administrative assistant, and Kristi A. Dobson, consultant, for their invaluable assistance in the planning and arrangements for this Indiana Conference, and Karen E. Wilczewski, Marketing Communications Consultants, for developing the camera-ready copy of this material.

PrefaceThis monograph contains the proceedings of the 7th Indiana Conference held July 3-5, 2005 at the Indianapolis Marriott Downtown Hotel, Indianapolis, Indiana, U.S.A. The program was designed as a workshop, with a series of presentations by recognized experts on assigned topics, followed by lengthy discussions by assigned discussion groups of 18 to 20 invited experts and conference attendees; final reports were then presented from each of the discussion groups. Six of the 12 primary oral presenters were from outside the United States, and the total of 150 invited scientists and conference attendees were from 18 different countries in North America, South America, Europe, and Asia. Copies of these oral presentations and the reports from the discussion groups are included in this monograph. This conference was made possible through grants from the National Institute of Dental and Craniofacial Research (Grant Number 1 R43 DE016767) and the Task Force for Design and Analysis in Dental and Oral Research. We are most appreciative for the support provided by these organizations. George K. Stookey, Ph.D. Distinguished Professor Emeritus Indiana University School of Dentistry

CLINICAL MODELS WORKSHOP: REMIN-DEMIN, PRECAVITATION, CARIES

i

II

INDIANA CONFERENCE 2005

Table of ContentsPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .i Table of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .iii List of Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vi Introductory Remarks & Workshop Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xi Paper Presentations Traditional Models for Clinical Caries Trials David Banting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Conclusions from the 2002 Scotland Concensus Conference (ICW-CCT) Nigel B. Pitts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17 ROC Analysis with Applications to Dental Research Nancy A. Obuchowski . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35 Including Non-cavitated Lesions in Pivotal Clinical Trials: Issues and Concerns Phillippe P. Hujoel, Walter Bretz, and James Bader . . . . . . . . . . . . . . . . . . . . . .49 Distinguishing Between Individuals with High or Low Risk of Developing Dental Caries Hannu Hausen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .65 Acceptance Criteria for Clinical Caries Models Albert Kingman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79 The Nyvad Criteria for Assessment of Caries Lesion Activity Bente Nyvad, V. Machiulskiene, and V. Baelum . . . . . . . . . . . . . . . . . . . . . . . . . . .99 The Chesters Model Using the Simplified DTSM Richard K. Chesters, I. Balciuniene, G. Matuliene, N.B. Pitts, and J.R. Matheson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117


III

The Biesbrock-Bartizek Caries Clinical Model Aaron R. Biesbrock, and R.D. Bartizek . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .143 Rationale and Evidence for the International Caries Detection and Assessment System (ICDAS II) Amid I. Ismail, and the International Caries Detection and Assessment System (ICDAS) Coordinating Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161 Appendix I. Criteria Manual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .190 Appendix II. Participants in the ICDAS Baltimore Workshop . . . . . . . . . . . . . . . . .209 Quantitative Light Induced Fluorescence in Caries Clinical Trials Susan M. Higham, I.A. Pretty, and P.W. Smith . . . . . . . . . . . . . . . . . . . . . . . . .223 Other Instrumental Detection Methods for Caries Clinical Trials James S. Wefel, Masatoshi Ando, and Jeffrey D. Harless . . . . . . . . . . . . . . . . .237 Workshop Procedures & Breakout to Workshop Groups Workshop Group on Statistical Modeling Strategies Albert Kingman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .251 The Nyvad Criteria Breakout Group Report Bente Nyvad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .257 2005 Indiana Conference Workshop Session: Chesters Model Richard Chesters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .259 2005 Indiana Conference Workshop Session: The Biesbrock-Bartizek Model Aaron R. Biesbrock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .263 Indiana Conference ICDAS Workshop Group Report Nigel B. Pitts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .265

IV


The Quantitative Light Fluorescence (QLF) Model Susan M. Higham . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .273 Other Instrumental Detection Methods for Clinical Caries Trials James S. Wefel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .277 Concluding Remarks George K. Stookey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .283


V

List of Participants

CONFERENCE HOSTDr. George K. Stookey Distinguished Professor Emeritus Indiana University School of Dentistry 1121 W. Michigan Street Indianapolis, IN 46202-5186 USA telephone: 001 317 278 7876 facsimile: 001 317 278 7880 e-mail: [email protected]

PRIMARY AUTHORSDr. David Banting School of Dentistry Faculty of Medicine & Dentistry University of Western Ontario London, ON N6A 5Cl Canada telephone: 001 519 661 2111, ext. 86130 facsimile: 001 519 661 3885 e-mail: [email protected] Dr. Aaron Biesbrock Procter & Gamble Company Health Care Research Center Mason, OH 45040-9462 USA telephone: 001 513 622 0316 facsimile: 001 513 622 0550 e-mail: [email protected]

VI


Richard K. Chesters Colgate-Palmolive Europe 13-15, Cours de Rive 1204 Geneva Switzerland telephone: 41 22 722 0784 facsimile: 41 22 722 0703 e-mail: [email protected] Dr. Hannu Hausen Institute of Dentistry P.O. Box 5281 FIN-90014 University of Lulu Finland telephone: 358 8 537 5582 facsimile: 358 8 537 5560 e-mail: [email protected] Dr. Susan M. Higham Cariology and Toothwear Research Group School of Dental Studies The University of Liverpool UK telephone: 44 0151 706 5251/5288 facsimile: 44 0151 706 5937 e-mail: [email protected]

Dr. Philippe Hujoel Department of Dental Public Health Sciences School of Dentistry University of Washington Seattle, WA 98195 USA telephone: 001 206 543 2034 facsimile: 001 206 685 4258 e-mail: [email protected]


VII

Dr. Amid I. Ismail Department of Cariology Restorative Sciences and Endodontics School of Dentistry, D2361 1011 N. University University of Michigan Ann Arbor, MI 48109-1078 USA telephone: 001 734 647 9190 facsimile: 001 734 936 1597 e-mail: [email protected] Dr. Albert Kingman Biostatistics Core Division of Clinical Research and Health Promotion National Institute of Dental and Craniofacial Research Bethesda, MD 20892-2190 USA telephone: 001 301 594 4820 facsimile: 001 301 480 8322 e-mail: [email protected] Dr. Bente Nyvad Faculty of Health Sciences University of Aarhus Vennelyst Boulevard 9 DK 8000 Aarhus C Denmark telephone: 45 8942 4074 e-mail: [email protected] Dr. Nancy A. Obuchowski Department of Quantitative Health Sciences.Wb4 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA telephone: 001 216 445 9549 facsimile: 001 216 444 3466 e-mail: [email protected]

VIII


Dr. Nigel B. Pitts Dental Health Services Research Unit & Centre for Clinical Innovations University of Dundee, Health Infomatics Centre Kirsty Semple Way Dundee DD2 4BF Scotland, UK telephone: 44 1382 635959 facsimile: 44 1382 226550 e-mail: [email protected] Dr. James S. Wefel Dows Institute for Dental Research College of Dentistry N413 DSB University of Iowa Iowa City, IA 52242 USA telephone: 001 319 335 7895 facsimile: 001 319 335 7376 e-mail: [email protected]


IX

X


Introductory Remarks & Workshop GoalsWelcome It is indeed my pleasure to welcome you to this Indiana Conference. This is the 7th Indiana Conference and has a somewhat different mission, format, and source of funding as compared to our previous conferences. The overall mission of the workshop is to review the status of various models being used for clinical caries trials. Funding for the entire workshop is being provided through grants from the National Institute for Dental and Craniofacial Research (Grant No. 1 R43 DE016767) and the Task Force for Design and Analysis in Dental and Oral Research. These grants allowed us to cover the costs for the primary speakers from academia and nearly all of the 58 invited expert discussants. We are most appreciative of these organizations for providing this support. We have limited attendance to 150, and we are pleased that we have a full house to address this important topic. Rather than a series of presentations on specific topics, this conference will follow a workshop format, with ample time for assigned group discussions of each topic. History of Indiana Conferences Indiana Conferences were initiated in 1996 as a means of having international scientists offer state-of-the-art presentations on selected topics and to provide a forum for scientists to discuss concerns and establish collaborations. The themes for the conferences have included early caries detection (1996, 1999, 2003), microbial pathogenesis (1997), dental and orthopedic implants (1998), and changing practices in restorative dentistry (2000). The proceedings of each conference has been published as a hard cover monograph and is provided to all attendees. Unrestricted funding to help cover travel costs for speakers and publication costs for these prior conferences were provided by the Procter & Gamble Company. The 2005 Indiana Conference is the fourth conference that has focused on the early detection of dental caries. Each of the previous conferences has involved a series of presentations by investigators of new and developing caries detection methods and technologies. These presentations have included virtually all of the technologies that have been, or are being George K. Stookey investigated for the detection of dental caries. CLINICAL MODELS WORKSHOP: REMIN-DEMIN, PRECAVITATION, CARIES XI

Technologies that have been presented and discussed have included fiber optic transillumination (FOTI), digital imaging fiber optic trans-illumination (DIFOTI), quantitative laser/light fluorescence (QLF), infra-red laser fluorescence (DIAGNOdent), dyeenhanced laser fluorescence (DELF), electrical conductance method (ECM), direct digital radiography (DDR), ultrasonic methods, polarization sensitive optical coherence tomography (OCT), multi-photon imaging systems, electro-mechanical approaches, infra-red photothermal radiometry, and infra-red thermography. Conference Goals It is well known that relatively few, if any, significant advances in the development of more effective measures for the prevention of dental caries have been identified during the past 25 years. As noted during the recent Scotland workshop, the primary reasons for this have been the relative inefficiency of accepted clinical models available for assessing the merits of improved caries-preventive agents or treatment strategies. This inefficiency has resulted in major costs, totaling several millions of dollars for a single controlled clinical trial, and a common time period of at least four years from initiation to final report. Needless to say, such a commitment of funding and time is extremely difficult to justify by either NIDCR or dental products manufacturers. Especially during the past three-to-four years, considerable attention has been given to the need to identify more efficient models for controlled clinical trials. In January 2002, Drs. Nigel Pitts and John Stamm organized an International Consensus Workshop on Caries Clinical Trials in Glasgow, Scotland, and the proceedings, which were recently published in a special issue of the Journal of Dental Research, emphasized the need for more efficient models for clinical caries trials. In May 2003, our most recent Indiana Conference involved a series of state-of-the-art presentations on current research involving early caries detection methods. In May 2004, NIH-NIDCR convened a major conference entitled Methods for Enhancing the Efficiency of Dental/Oral Health Clinical TrialsCurrent Status, Future Possibilities, which focused on efforts to develop surrogate markers and other strategies to improve the efficiency of clinical trials. These prior conferences, as well as numerous literature reports, have recognized that the caries process is a continuum, beginning with enamel demineralization and progressing over a period of time to cavitation. While actual cavitation has been the measurable end-point in traditional clinical caries trials, it is recognized that this late stage of the caries process is no longer acceptable as the primary assessment measure, and there should be earlier stages in the process that may be used for this purpose. Dental scientists have proposed several approaches to improving the efficiency of clinical caries trials. These approaches have included:

XII


increased supervision and control of panelist compliance with the treatment regimens required of the investigation; clinical assessments of the caries process at the pre-cavitation stage of development; and, the use of instrumental methods capable of detecting and monitoring the caries process at the early enamel demineralization stage, well in advance of cavitation. During the past few years, several controlled clinical caries trials have included these methodologies, and the results of several of these investigations have been published or have become available at different conferences. The 2005 Indiana Conference has been designed as a workshop for established cariologists to review the available supporting data and determine whether there are now more efficient clinical models available for future assessments of caries-preventive measures. Thus, the goals of this workshop are to: review the scientific information available for the different strategies that have been explored to improve the efficiency of controlled clinical caries trials; and, determine whether there are adequate data to support the use of these methodologies in future clinical trials of caries-preventive measures and, if not, the type of additional information that is needed for these approaches. Workshop Format The format for this workshop will involve a series of presentations by persons considered to be among the leading experts on the designated topic, followed by workshop discussions of each topic by 18 to 20 invited scientists and general workshop participants. The designated topics include several presentations considered to be important background reviews for the discussions and presentations of the following clinical models: Statistical Modeling Strategies The Nyvad Model The Chesters Model The Biesbrock-Bartizek Model The ICDAS Model QLF: Quantitative Light Fluorescence Other Models for Clinical Trials The workshop will conclude with reports and recommendations from each of the discussion groups. We expect that these discussions and recommendations will be very important for identifying scientifically acceptable clinical models for future clinical caries trials.


XIII

XIV


Traditional Models for Clinical Caries TrialsDavid Banting School of Dentistry, Faculty of Medicine & Dentistry, University of Western Ontario, london, Ontario, Canada

Introduction One good thing about being around for a long time is that it affords one a unique perspective, an opportunity to judge events over time, which is not otherwise possible. I had the privilege a few years ago to speak at Don Lewis retirement and remarked then that, in the field of health services research, concepts that Don Lewis and other visionaries were researching, presenting, and promoting 30 years ago are now being widely accepted and implemented; concepts like critical appraisal of the literature, quality assessment, and the evidence-based approach.

The Traditional Models for Clinical Caries Trials Just last year, Ismail [2004] conducted a systematic review of criteria systems used for the detection and classification of dental caries from 1950 to 2000. This was the first time that the content validity of these existing systems had been looked at. What I found fascinating about this review was that it revealed 29 unique criteria systems and then went on to discuss their origin, date of introduction, and the criteria used. Ismail also made some interesting observations concerning whether or not these systems measured both the active and inactive stages of the caries process, whether an explorer was used for probing, and whether the teeth were cleaned and dried prior to applying the criteria. There are 3 messages resulting from this review that I feel are pertinent to this presentation: 1. There was considerable variability in the disease processes measured by the different systems.


1

BANTING

2. Generally, European systems include both the non-cavitated (early) and advanced (cavitated) stages of the caries process; whereas, North American systems focus on measuring cavitated lesions. 3. The sensibility of the European criteria is towards characterizing the disease process; whereas, the sensibility of the North American system is towards achieving reliability of caries diagnosis. Rightly or wrongly, I have selected 3 of these 29 systems as the traditional models. These models were developed in the 1960s, 1970s, and 1980s and have, as far as I can determine, been widely used throughout the world in clinical trials and surveys relating to dental caries. The 3 models that I have designated as traditional models are Radikes criteria [1968], the WHO Oral Health Surveys Basic Methods criteria [1971], and the NIDR criteria [1987].

Radike Criteria for Diagnosis of Dental Caries The Conference on Clinical Testing of Cariostatic Agents was convened at the American Dental Association in October 1968. Some in the audience were fortunate to be a part of that conference. When you look down the list of names of conference attendees, you cannot help but be impressed with who was there. I will not name them all, but names such as Finn Brudevold, Neal Chilton, Bob Grainger, Hershel Horowitz, Hans Muhlemann, Charles Gish, Stan Heifetz, Walter Zackeral, James Carlos, Thomas Mathaler, Harold Englander, Robert Glass, Geoffery Slack, Paul DePaola, Louis Ripa, George Stookey, and Tony Volpe are names we associate, not only with dental caries, but with clinical studies of dental caries. Arthur Radike worked for the Procter & Gamble, and he presented 2 papers at the 1968 ADA conference. The first paper was entitled, Criteria for the Diagnosis of Dental Caries and the second paper was entitled, Examiner Error and Reversals in Diagnosis. Although the first paper is the major focus of this presentation, I will refer to both papers. Radikes paper on Criteria for Diagnosis of Dental Caries was actually a report of a Task Group on Caries Management that had gathered together for several work sessions in the year preceding the conference; The Task Groups report was reviewed during the conference and ultimately appeared in a well known ADA document entitled, Proceedings of the Conference on Clinical Testing of Cariostatic Agents that was published 4 years later in 1972.2 INDIANA CONFERENCE 2005

TRADITIONAL MODELS

FOR

CLINICAL CARIES TRIALS

The criteria, which became known as Radikes criteria, gave us such familiar descriptors for dental caries as a frank lesion, gross cavitation, the catch of an explorer, and a discontinuity or break in the continuity of the enamel surface. All of these, you will notice, deal with a hole in the tooth.

WHO Criteria In 1961, the World Health Organization (WHO) convened a WHO Expert Committee on Dental Health and formulated standard methods for the reporting of dental diseases (WHO, Technical Report Series, 1962, No. 242). This was followed a decade later by a manual on Basic Methods for Oral Health Surveys. As part of that manual, criteria for diagnosing dental caries were presented. These criteria are, no doubt, equally as familiar as that of Radike to most people in this audience. With the WHO criteria, in order for caries to be detected, a lesion must have a detectably softened floor, undermined enamel or softened wall. On an inter-proximal surface, the probe point must enter a lesion with certainty. The WHO criteria specifically stated: where any doubt exists, caries should not be diagnosed as present.

NIDR Criteria The 1987 version of the NIDR criteria were based on criteria developed in 1938 by H.T. Klein, C.E. Palmer, and J.W. Knutson for the DMFT index. However, the NIDR criteria also provided for the detection of what was termed incipient lesions and subdivided these into 3 categories according to location: pits and fissures, smooth areas on buccal and lingual surfaces, and proximal surfaces. The NIDR criteria described carious lesions on the root surfaces of teeth for the first time. Carious lesions that occur on the roots of teeth were described a being discolored, either with or without cavitation present. An explorer was used to detect a softness to the lesion. Rules were provided to determine whether adjacent coronal surfaces were to be deemed carious and to determine whether adjacent root surfaces were also carious.


3

BANTING

Characteristics of the Traditional Models for Caries Detection The details of the criteria for each of these traditional models can be found in the appendices and will not be reviewed in detail. However, it is informative to contrast some of the characteristics of these traditional models in order to illustrate not only similarities, but some evolution in the detection procedure. The Radike and WHO criteria relate only to coronal surfaces. The NIDR criteria included criteria for both coronal and root surfaces. All 3 of these models considered only cavitated lesions as caries. This is very much a North American sensibility, as Ismail has aptly pointed out. The NIDR criteria, however, include both gross and incipient lesions as caries, but the explorer must be used, and there must be softnessdetected by tactile sensation. Unfortunately, none of these models evaluate carious lesion severity or depth. No distinction is made between carious lesions that involve only the enamel or those that extend into the dentine and, except for white spots lesions that are soft to the explorer touch in the NIDR criteria, enamel lesions are precluded from all of these models. The Radike and NIDR procedures recommend that the teeth be dry when viewed, and the WHO procedure does not mention drying the teeth, probably because it is designed to be used under field conditions. All 3 detection models advocate that a (sharp) explorer be used with moderate-to-firm pressure for tactile purposes; all 3 ignore any judgment regarding lesion activity, and all 3 specify conditions, primarily stain, and white spots that are not defined as dental caries (Table 1).Model Surfaces Evaluated Stages Measured Severity cavitated Lesion Depth or Wet or Dry no Explorer Used/Viewed Activity Other Conditions Excluded stain, pigmentation, fractures, erosion, abrasion, hypoplasia, mottled enamel, certain enamel opacities white or chalky spots, discolored or rough spots, hard pits or fissures that catch on the explorer point stain, hypoplasia, sealants

Radike

coronal

yes/dry

no

WHO

coronal

cavitated

no

yes/wet

no

NIDR

coronal and root

cavitated

no

yes/dry

no

TABLE 1. 4

Characteristic of the traditional caries detection models. INDIANA CONFERENCE 2005

TRADITIONAL MODELS

FOR


The Reality of Dental Caries Detection and Classification Today Since these traditional models were developed, our thinking about dental caries has evolved such that there are 10 principles that I feel reflect todays reality about dental caries 1. dental cariesa continuum: a process that begins with the loss of ions and ultimately ends with destruction and loss of 1 or more of the 3 calcified tissues of the tooth. 2. intermediatein this continuum there is a non-cavitated stage of dental caries (with substages) that can be identified and described using clinical signs [Ekstrand, 2004]. 3. superimposed on all of this is the notion that the dental caries process is reversible (demineralization/remineralization), at least in its early stages and that the surface contour, once lost, cannot be naturally re-established. 4. the time it takes for dental caries to progress/regress from one stage to another and through any stage is widely variable among individuals and groups. 5. surgical intervention (restoration) is generally considered to be a last resort in the management of dental caries, and the mere presence of cavitation does not necessarily invoke this type of management. 6. a carious lesion can either be in an active state or an inactive state at any one point in time. 7. there is a cut point, a point before which dental caries cannot be detected clinically using visual criteria. 8. the use of tactile sensation using a sharp instrument with moderate pressure is only marginally useful for detection and may adversely affect the carious lesion. 9. measurement of dental caries prevalence should take into account both non-cavitated and cavitated lesions. 10. similarly, measurement of dental caries incidence or increment should take into account transitions between all the clinical stages in the dental caries continuum, including biologically plausible reversals (remineralization).


5

BANTING

The Traditional Caries Detection Models and Todays Reality So, how well do the traditional models for diagnosing dental caries fulfill our present day needs for caries detection? Clearly, the Radike and WHO models do not provide any information on non-cavitated carious lesions or carious lesions on the roots of teeth. Investigators today want to know not only whether or not caries is present and on what tooth surface(s), but they need to know how severe the lesion is, whether it is active or arrested, and whether it is progressing or improving with treatment (remineralizing) in order to provide an accurate and valid picture of what is happening and initiate and evaluate different management strategies. It is readily apparent that all 3 of the traditional dental caries detection models fall short of what is needed to meet current needs regarding the detection of dental caries (Table 2). Therefore, we need to develop new models of visual caries detection. This is perhaps more easily said than done, because these new models would need to possess, at minimum, the following characteristics: 1. be backwardly compatible with traditional caries detection models for comparative purposes. 2. encompass the full range of conditions or stages deemed to be clinical dental caries. 3. be shown to be reproducible (reliable) at a specified level. 4. be valid.

Requirements Non-cavitated lesion coronal root Cavitated lesion coronal root

RADIKE

WHO

NIDR

no no yes no

no no yes no

yes yes yes yes

Severity (depth) Activity (progresses/arrests) Treatment options

RADIKE no no

WHO no no

NIDCR no no

surgical only

surgical only

medical and surgical

TABLE 2.

Traditional caries detection models and present-day measurement and reporting requirements. INDIANA CONFERENCE 2005

6

TRADITIONAL MODELS

FOR


differentiate active from arrested or remineralized lesions. incorporate severity levels that can be directly translatable into treatment management protocols. 7. be versatile in order to meet the specific needs of epidemiology/public health, research, and clinical practice. Even if new models were developed that met these guidelines, there are several issues related to dental caries detection that remain unresolved, and the resolution of these issues should precede the development and/or acceptance of any new diagnostic criteria for dental caries. These issues are: 1. a clear distinction between the use of the terms detection and diagnosis, guidance as to when each should be used, and what type of personnel can credibly perform these tasks. 2. clearly defined cut points in the dental caries continuum that can be directly translated into clinical decisions regarding observation, medical management, and surgical management of dental caries. 3. updating of undergraduate dental programs regarding current evidence relating to the detection and diagnosis of dental caries. 4. guidance and education of the dental profession as to when and how adjunctive clinical tests (laser fluorescence, FOTI, ultrasound) should be used to supplement the clinical detection/diagnosis of dental caries. 5. guidelines regarding the measurement and reporting of dental caries increment in clinical studies of anti-caries agents that are capable of arresting and/or reversing (remineralizing) a caries lesion.

5. 6.

A Final Word About the Measurement of Caries Increment My final comments relate to the last point. Radikes second paper at the Conference on the Clinical Testing of Cariostatic Agents dealt with examiner agreement or reproducibility. For anyone involved in clinical caries studies, this is a critical issue. In his paper, Radike made the point that, with the criteria that the Task Group proposed for the diagnosis of dental caries, errors would occur in an


7

BANTING

examiners calls, particularly reversals in diagnosis. And, Radike made the further point that these reversals will be more prevalent in the transition zone between sound and carious enamel. In fact, Radike estimated that 25% of the conditions in this transition zone will result in a reversal in diagnosis. Measurement of caries increment must take into consideration: 1. examiner inconsistency related particularly to non-cavitated lesions, 2. remineralization as a plausible treatment outcome, and 3. length of the observation period. One of the justifications for detecting earlier (non-cavitated) stages of dental caries is to shorten the observation period. This has the obvious advantage of clinical trial efficiency, with the accompanying funding implications. However, in order to determine what is actually happening in a clinical trial, a longer observation time may actually be required. For instance, consider the possible examination-to-examination transition strings for a given tooth surface (table at the top of page 9). A single (usually 6-month) examination can only provide information on a single transition, and the validity of that transition cannot be determined. Longer observation periods allow for more transitions, which, in turn, provide more information. However, at the same time, other measurement dilemmas are introduced such as: 1. When does a transition string become an increment? 2. What constitutes a plausible treatment reversal? 3. What is an illogical reversal? 4. How do you differentiate a treatment reversal from an examine error? 5. How many repeat calls are needed to ensure the validity of a call? 6. How is lesion activity determined? These are the fascinating and, in my mind, vital issues to be addressed in clinical visual detection of dental caries today. And, just to confuse things a bit further, caries increment can be calculated in several different ways, depending on whether reversals are included and whether or not more than 1 event can take place on a given surface over time. Some possible caries increment measures include:

8


TRADITIONAL MODELSTransition String S, D1w S, D1w, D1d Observation Time 6 months 12 months A positive increment

FOR


What is Going On?

A positive increment followed by a plausible reversal (negative increment) OR A positive increment followed by an examiner error Should 2 positive and 1 negative increment be counted here? OR Is there just 1 positive increment with an examiner error that should be ignored?

S, D1w, D1d, D1w

18 months

S, D1w, D1d, D1w, D2

24 months

There is obvious progression of the lesion but: Which end point(s) do you count? To what stage do you allow the lesion to progress without treatment?

S, D1w, D1d, D1w, D2, D1w

30 months

Was the 24-month call an examiner error? OR Is this a plausible reversal (negative increment)?

D1d, S D1d, S, D1d

6 months 12 months

Starting with an early lesion, is this a negative increment (reversal)? Has this lesion become active again or was the 6-month call an examiner error? How do you score this? Is this a single, positive increment or a series of positive and negative increments? Does consistency of the call at 24- and 30 month examinations confirm that there was a positive caries increment at 24-months?

D1d, S, D1d, S D1d, S, D1d, S, D2 D1d, S, D1d, S, D2,D2

18 months 24 months

30 months

F, S

6 months

An obvious illogical transition; however, which call is correct if the trial does not continue?

Crude Incrementfirst event/surface, reversals not included Crude Cumulative Incrementmultiple events possible/surface, reversals not included Net Incrementfirst event/surface, reversals included Net Cumulative Incrementmultiple events possible/surface, reversals included I do not believe that any consensus exists as to which caries increment measure is considered to be the most appropriate. Actually, the most appropri-


9

BANTING

ate measure may depend on several factors that may vary among clinical trials. The traditional models of caries detection, as faithfully as they have served us for the past 30 years, can no longer help us with the measurement issues we face today. It is time to move on.

ReferencesEkstrand KR: Improving clinical visual detection-potential for caries clinical trials. J Dent Res 2004;83(Spec. Issue C): C67-C71. Ismail, A: Visual and visual-tactile detection of dental caries. J Dent Res 2004;83(Spec. Issue C): C56-C66. Proceedings of a Conference on the Clinical Testing of Cariostatic Agents 1968. World Health Organization, Oral Health Surveys, Basic Methods, Geneva: World Health Organization 1971. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Oral Health of United States Adults, NIH Publication No. 87-2868, August 1987.

10


TRADITIONAL MODELS

FOR


Radikes Criteria (1968)I. Frank lesions gross cavitation (defined as a discontinuity of the enamel surface caused by loss of tooth substance) is present. cavitation must be distinguished from fractures and smooth lesions of erosion and abrasion. Lesions not showing frank cavitation Pits and fissure lesions of the occlusal, facial, and lingual surfaces. 1. area is carious when the explorer catches or resists removal after insertion into a pit or fissure using moderate to firm pressure and when accompanied by 1 or more of the following signs of caries: a softness at the base of the area opacity adjacent to the pit or fissure as evidence of undermining or demineralization softened enamel adjacent to the pit or fissure, which may be scraped away with an explorer 2. the area is carious if there is loss of the normal translucency of enamel adjacent to the pit, which is in contrast to the surrounding tooth structure Lesions on smooth areas of facial and lingual surfaces 1. area is carious if the surface is etched or if there is a white spot as evidence of subsurface demineralization and if the area is found to be soft by: penetration with an explorer scraping away enamel with an explorer 2. area is sound when there is apparent evidence of demineralization (etching or white spot) but no evidence of softness Lesions on proximal surfaces 1. for areas exposed to direct visual and tactile examination, these lesions are diagnosed with the same criteria as smooth lesions on facial and lingual surfaces 2. for hidden areas not exposed to direct visual-tactile examination:11

II A.

B.

C.


BANTING

- if the marginal ridge shows an opacity as evidence of undermined enamel, the proximal surface is carious - any discontinuity of the enamel in which an explorer can enter is carious if it also shows other evidence of decay, such as: softness, shadow by transillumination, or loss of translucency - with radiographs, any definite radiolucency, indicating a break in the continuity of the enamel surface is carious - with transillumination, a loss of translucency producing a characteristic shadow in a calculus-free and stain-free proximal surface, is adequate evidence of caries It is interesting to also examine some of the caveats that the Task Group placed on these criteria. For instance, the report indicated that: Not every member agreed on all aspects of diagnosis. More variability was found in the examination procedures used for proximal surfaces than for other surfaces. Lesion depth is not a component of these criteria. Stain and pigmentation should not be regarded as evidence of caries since they occur in sound teeth. In borderline conditions, a decision to classify as sound or carious must be made. When in doubt, call it sound. Erosion, abrasion, hypoplasia, attrition, fractures, mottled enamel, and certain enamel opacities on exposed hard surfaces should not be classified as caries.

12


TRADITIONAL MODELS

FOR


WHO Basic Methods (1971)A. caries will be considered present in a tooth when any lesion has a detectably softened floor, undermined enamel, or a softened wall. B. on an interproximal surface, the probe point must enter a lesion with certainty. The caveats that WHO placed on its criteria were: Where any doubt exists, caries should not be diagnosed as being present. The stages that precede cavitation and other conditions similar to the early stages of caries should be deliberately excluded, because they cannot be diagnosed positively and reliably. Defects not to be counted as caries are: (1) white and/or chalky spots, (2) discoloured or rough spots, and (3) hard-stained pits or fissures in the enamel that catch on the explorer point but do not have a detectably softened cavity, undermined enamel, or softening in the walls of the pit or fissure.


13

BANTING

NIDR Criteria (1987) Coronal CariesFrank lesions are detected as gross cavitation. Incipient lesions may be subdivided into 3 categories according to location, each with special diagnostic considerations. These categories are: A. pits and fissures on occlusal, buccal, and lingual surfaces: these areas are diagnosed as carious when the explorer catches after insertion with moderate to firm pressure and when the catch is accompanied by 1 or more of the following signs of decay: i. softness at the base of the area. ii. opacity adjacent to the area, providing evidence of undermining or demineralization. iii. softened enamel adjacent to the area, which may be scraped away with the explorer. B. smooth areas on buccal (labial) or lingual surfaces: these areas are carious if they are decalcified or if there is a white spot as evidence of subsurface demineralization and if the area is found to be soft by: i. penetration with the explorer, or ii. scraping away the enamel with the explorer. These areas should be diagnosed as sound when there is only visual evidence of demineralization, but no evidence of softness. C. proximal surfaces: for areas exposed to direct visual and tactile examnation, as when there is no adjacent tooth, the criteria are the same as those for smooth areas on facial or lingual surfaces. For areas not available for direct visual-tactile examination, the following criterion applies: a discontinuity of the enamel in which the explorer will catch is carious if there is softness. In posterior teeth, visual evidence of undermining under a marginal ridge is not acceptable evidence of a proximal lesion unless a surface break can be entered with the explorer. In anterior teeth, however, transillumination can serve as a useful aid in discovering proximal lesions. If a characteristic shadow or loss of translucency is seen on the proximal surface, this is indicative of caries on that surface. Ideally, the actual diagnosis should be confirmed with the explorer; however, clear visualization of a lesion by transillumination can justify a positive diagnosis.

14


TRADITIONAL MODELS

FOR


Root Surface Caries Active carious lesions in root surfaces are yellow/orange, tan, or light brown in color. Lesions in remission tend to be darker, sometimes almost black. In some incipient lesion, the carious area of the root surface may merely be discolored without cavitation, but the area will be soft to exploration. Cavitation with jagged margins and a roughened, but soft floor or base usually occurring in advanced (lesions), will yield to pressure from the tip of an explorer. Areas of root caries, however, are softer than surrounding cementum; therefore, it is possible to differentiate sound from carious cementum based on tactile sense. In the presence of root caries, an explorer penetrates the tissue but usually can be removed easily. However, if the explorer penetrates but resists withdrawal or sticks, the surface is usually sound cementum. N.B. for areas without gross cavitation, visual criteria related to location, shape, and discoloration of the suspected area do not, in themselves, define root caries. The tactile criteria of softness to an explorer tip must be met for a definitive diagnosis of root caries to be made.


15

16


Conclusions from the 2002 Scotland Consensus Conference (ICW-CCT)**Based on a presentation made at the Indiana ConferenceClinical Models Workshop: Remin-Demin, Precavitation, Caries.

Nigel B. Pitts Dental Health Services Research Unit and Centre for Clinical Innovations, University of Dundee, Scotland, UK

Abstract Conclusions from the 2002 Scotland Consensus Conference Introduction: The International Consensus Workshop on Caries Clinical TrialsAgreeing Where the Evidence Leads (ICW-CCT) reached consensus on caries clinical trials that are scientifically acceptable as pivotal evidence of the anti-caries efficacy of oral care products. Methodology: Twentyfive review papers were debated over 3.5 days by 95 participants from 23 countries to meet the workshop objectives (to critically review modern caries definitions and concepts, the evidence on caries-diagnostic methods, potential designs for modern caries clinical trials, and the statistical approaches to analyzing modern trial data) and formulate key elements of protocol(s) for shorter, more efficient modern caries clinical trials and a framework for validating them endorsed by the group of leading international experts present at the meeting. Results: Key Consensus Statements: Caries assessment methods: in future CCT protocols, caries measurement methods are used that are capable of accurately capturing, at any given point in time, the manifestations of the caries process in dental hard tissues (enamel and dentin); when applied sequentially, these caries assessment methods can monitor definitive changes in manifestations of the caries process over time, over and above any background noise from normal levels of de- and remineralization, or from variations attributable to the caries detection system(s) used; and when applied sequentially, they can differentiate from among actual product effects in terms of group differences in lesion initiation and lesion behaviour (progression, arrest, and/or regression). If they are


17

PITTS

valid and contribute to the ability to improve trial efficiency, the new caries assessment technologies should be refined further and adopted in modern caries clinical trials. Validation of new assessment methods with clinical trials: Methods capable of recording the continuum of the caries process (including non-cavitated lesions) should be evaluated and their results compared with those of conventional caries assessment methods over a 2- to 3-year study; new caries assessment methods should have the ability to measure demineralization and remineralization of noncavitated lesions; while there are many other ways in which the design of CCTs might be improved further, through better diagnostic, design, and analytical techniques, it is paramount that the overriding principle behind CCT design validation must be that the results and conclusions from any new design are in line with those shown previously by conventional CCTs; any new design of caries clinical trial must not compromise the standard of proof of either efficacy or safety.

Introduction The International Consensus Workshop on Caries Clinical Trials Agreeing Where the Evidence Leadswas held at Cameron House on the shores of Loch Lomand, Scotland, between January 6-10, 2002. The Workshop was jointly organised and co-chaired by Nigel Pitts of the University of Dundee and John Stamm of the University of North Carolina and supported by the International Association for Dental Research (IADR), The National Institute for Dental and Craniofacial Research (NIDCR), the International Dental Federation (FDI), and major dentifrice companies. The Scientific Programme Committee comprised the co-chairs and representatives of all the supporting organisations. The purpose of this paper is to set the scene for the 2005 Indiana ConferenceClinical Models Workshop by providing an overview of what happened at the 2002 International Consensus Workshop on Caries Clinical Trials, ICW-CCT. The Mission of the 2005 Indiana Conference states: The Primary purpose of this Indiana Conference is to follow-up and build upon the results of the 2002 Loch Lomand Conference. The overall goal of the 2005 conference/workshop is to develop a general consensus among the scientific com

18


CONCLUSIONS FROM THE 2002 SCOTLAND CONSENSUS CONFERENCE (ICW-CCT)

munity regarding the acceptability of new, more efficient models for clinical trials designed to assess the impact of caries-preventive measures on remineralization, precavitation, and caries. Although the entire proceedings of the 2002 ICW-CCT Workshop are now published in a supplement to the Journal of Dental Research for reference [Pitts and Stamm, 2004], this paper highlights the main points and key Consensus Statements relating to the Indiana Conference. There is, however, much valuable detail in the 25 individual review papers that are published, in addition to the final Consensus Statements in this special issue.

Methodology: The ICW-CCT Process The Mission of the International Collaborative Workshop on Caries Clinical Trials (ICW-CCT) was to reach consensus about the design of protocols for caries clinical trials that are scientifically acceptable as pivotal evidence of the anti-caries efficacy of oral care products. A recurring theme of the ICW CCT was the desirability of identifying and evaluating methods that would lead to valid and reliable, yet shorter, more efficient caries clinical trials. The Scientific Programme Committee assembled an international panel of 25 speakers to review and present the contemporary evidence from across the disciplines who are concerned with improving the quality and efficiency of clinical trials for caries preventive agents and procedures. This evidence was then debated at length in a series of facilitated and repeated discussion sessions over 3.5 days by 95 participants from 23 countries. There was international representation from academia, industry, statisticians, methodologists, and regulators. Draft Context and Consensus Statements about the evidence and key elements of the design of future trials were presented to, debated, modified, and finally agreed upon by all participants on each evening and on the final morning. The papers outlining the reviews were then peer-reviewed prior to publication. To accomplish the ICW CCT mission and structure of the Workshop, the following 5 following objectives were set out for participants: 1. Critically review modern caries definitions and measurement concepts. 2. Critically review the evidence on caries diagnostic methods. 3. Debate potential designs for modern caries clinical trials to provide pivotal evidence of anti-caries activity.CLINICAL MODELS WORKSHOP: REMIN-DEMIN, PRECAVITATION, CARIES 19

PITTS

Critically review the statistical approaches that could be used to analyze modern caries clinical trial data. 5. Ensure that, in meeting objectives 1-4 identified in the Workshop, participants formulate key elements of protocol(s) for shorter, more efficient modern caries clinical trials and a framework for validating them be endorsed by the leading group of experts present at the meeting. The full list of review papers that were presented to inform discussion is set out in the Journal of Dental Research Supplement. Presentations relating directly to the aims of the 2005 Indiana Conference included those on: NIH Consensus Development Conference on the Diagnosis and Management of Dental Caries throughout Life Washington D.C., March 2001 [Horowitz, 2004] The international evidence base for the continuum of the caries process [Featherstone, 2004] and the histopathology of caries related to biofilm [Kidd and Fejerskov, 2004] A systematic approach to visual caries detection [Ismail, 2004] Modern methods of caries measurement [Pitts, 2004] The potential of optical methods [Stookey, 2004] The potential of electrical methods [Longbottom and Huysmans, 2004] When designing clinical trials, it is important to understand the clinical context in which preventive caries control interventions are now delivered. Figure 1 shows a graphic representation of the 3 types of modern caries measurement: lesion measurement (assessing the extent of the lesion from early to later stages), lesion monitoring (assessing the behavior of lesions over time), and caries activity measures (which assess whether a lesion is active at a particular time point) [Pitts, 2004]. This focus on control of early stages in the disease process has been responsible for an increased focus on white (and brown) spot lesions of caries in enamel. Figure 2 shows clinical examples of non-cavitated (or pre-cavitated) caries lesions.

4.

20



FIG. 1.

Three types of modern caries measurement.

FIG. 2.

Non-cavitated or pre-cavitated caries is caries; it is amenable to preventive care, which minimises future fillings and future costs. 21


PITTS

Results of the ICW-CCT Process Consensus Statements for Objective 1: Critically Review Modern Caries Definitions and Measurement Concepts Context Dental caries is a process involving an imbalance of the normal molecular interactions between the tooth surface/subsurface and the adjacent microbial biofilm. This imbalance is manifested over time as cumulative demineralization of the tooth, which, if unchecked, has the potential to produce cavitation of the enamel and collateral damage to the dentin and pulp. Active caries is a process whereby an overly acidic environment caused by the presence of cariogenic organisms fuelled by the consumption of fermentable carbohydrates leads to the relatively rapid net destruction of hard tooth structure. Enamel caries, root caries, and dentinal caries are all variations on the same theme of bacterially induced demineralization and proteolysis. Consensus Statements (1.1) The Caries Process occurs as an interaction between biofilm and the tooth surface and subsurface. The Caries Lesion is the manifestation of the stage of the process at one point in time. [Note to readers: For clinical and epidemiological purposes, it is useful to know at one point in time whether a lesion is active, but within the clinical trial context, consecutive measures of lesion behavior provide sufficient information to establish efficacy between products.] (1.2) Caries progression occurs when the demineralization and remineralization equilibrium is out of balance, leading to net mineral loss. (1.3) Remineralization can arrest or reverse progression of disease and can lead to changes in mineral quality. (1.4) An understanding of the caries process has progressed far beyond the point of restricting evidence for dental caries to the D2 (caries in enamel only) or D3 (caries in enamel and dentin) level of cavitation. (1.5) One of the desired outcome measures in future caries clinical trials should be the arrestment or reversal of the progress of mineral loss. (1.6) Caries in enamel, dentin, and on root surfaces are all variations on the same theme of bacterially induced demineralization, alternating with remineralization, over many cycles in a lifetime.22 INDIANA CONFERENCE 2005

m p t n


OBJECTIVE 2: Critically Review the Evidence on Caries-diagnostic Methods Context Existing caries-diagnostic methods used for many years in clinical practice and in clinical caries trials have centered on either clinical visuo-tactile or, in Europe in particular, clinical visual examinations. Since clinical examinations alone were shown to be relatively insensitive (although highly specific), they have often been supplemented in trials with bitewing radiography and, in some countries, Fiber-Optic Transillumination (FOTI). There have been attempts over many years to find improved methods of caries detection, and ordinally graded or continuous measures of mineral density have been developed or are under development for the measurement of net mineral loss in caries lesions over time. Proposed measures are based on disciplined standardized observation according to established techniques, technologically enhanced visual observations, new imaging technologies, and different combinations of these. There is some confusion with the terminology used in the literature around caries diagnosis (which should imply a human professional summation of all available data), lesion detection (which implies some objective method of determining whether or not disease is present), and lesion assessment (which aims to characterize or monitor a lesion, once it has been detected). Consensus Statements Existing Methods of Caries Detection and Assessment (2.1) For future clinical trials, recording only cavitated lesions as an outcome measure is becoming outmoded. (2.2) Visual inspection is the standard of caries diagnosis in Europe. Its use should continue to be evaluated in clinical trials to differentiate between stages of the carious process in different surfaces. A systematic review of the varied criteria for clinical visual assessment would help to build on the extensive literature already available. Detailed protocols for training and calibration with visual-only examination systems should be established and tested. The aim


23

PITTS

(2.3) (2.4)

(2.5) (2.6)

is to consistently achieve the high levels of inter- and intraexaminer agreement shown to be possible with such systems. The use of additional methods of caries lesion assessment to supplement visual techniques should be explored further. Bitewing radiography may add information about many of the clinical stages of the carious process at approximal surfaces and, in the case of more advanced stages, occlusal surfaces. Diagnostic yield with contemporary caries presentations must be evaluated and, for use in caries clinical trials, the prospects of radiographic examinations adding to product discrimination should be assessed. Low-dose radiographic systems and/or subtraction radiography should be considered when radiography is used for caries trials. Fiber-Optic Transillumination (FOTI) has been used successfully for caries diagnosis in some countries. Its wider use in caries clinical trials should be considered.

Validation of Methods of Caries Detection and Assessment (2.7) In vitro and/or in situ studies are still required, both should be instituted to develop and to evaluate new diagnostic techniques. (2.8) For extrapolation of the results of laboratory studies on caries diagnostic techniques to clinical use, the clinical environment, e.g., soft-tissue equivalents, moisture, etc., should be simulated as closely as possible within the laboratory setting. (2.9) There is concern about the so-called gold standards currently used in caries diagnosis/detection research, particularly for assessing occlusal and approximal surfaces. (2.10) Given the deficiency of current gold standards, and the challenges related to achieving appropriate validation, new reference standards and validation protocols should be developed. When the accuracy and precision of new caries-diagnostic methods are determined, it is necessary that the distribution of caries lesions in the in vitro or in situ assessment include all disease stages in which the diagnostic method will be used in vivo. (2.11) It should be appreciated that validation studies using immature teeth or only premolars and third molars may not be sufficiently representative to provide accurate and precise data for validation purposes.24 INDIANA CONFERENCE 2005


Newer Methods of Caries Detection and Assessment (2.12) The assessment of non-cavitated lesions is essential for future CCTs, and new caries assessment methods have the prospect of helping in this task. (2.13) It would be desirable that the stage at which the carious process is measured with new diagnostic techniques relate to the extent to which the particular technique has been validated at the corresponding level of sensitivity. (2.14) New assessment techniques should, in the clinical context, be capable of measuring a wide range of lesion depths and changes in degree of mineralization, either directly or indirectly. Ideally, a continuous scale should be used. (2.15) The inherent nature of some of the techniques restricts surface types, which can be assessed, and the range of lesions, which can be measured. (2.16) Ideally, new caries assessment technologies should have the capacity to monitor changes on a highly targeted surface and on a sitespecific basis. (2.17) New measurement methods should continue to be developed. Electro-physical agents and other waves may have the potential to detect lesions and quantify changes in the caries process. Current examples are in various stages of development and include Electronic Caries Monitors (e.g., ECM), DIAGNOdent, Quantitative Light Fluorescence (QLF), Digitized Fiber Optic Transillumination (DIFOTI), and Optical Coherence Tomography (OCT). Other techniques are under development. (2.18) The new technologies should be further refined and adopted in modern caries clinical trials if they demonstrate the ability to improve trial outcomes, reduce subject numbers, and/or reduce costs. (2.19) Since some trials may, in the future, be conducted in general practice settings, and in order to optimize translation of research into practice while minimizing the risk of over-prescription, developers of new diagnostic techniques should specify the appropriate uses in caries clinical trials and/or in dental practice.


25

PITTS

(2.20) The importance of assessing newly erupted teeth with immature enamel and their related challenges should be recognized fully. (2.21) All new methodologies should have an in vitro assessment on natural caries lesions as part of the validation process. (2.22) Some new diagnostic techniques may exceed the accuracy, sensitivity, and resolution of existing validation reference standards. (2.23) Further investigation into how new technologies assess root, recurrent/secondary, and residual caries is required. (2.24) This field should be reviewed periodically to chart developments in technology and determine whether the new methods can improve on current methodology in the caries clinical trial context. OBJECTIVE 3: To Debate Potential Designs for Modern Caries Clinical Trials to Provide Pivotal Evidence of Anti-caries Efficacy Context Since the fundamental caries process varies only in detail across lesion sites and depths, and since surface demineralization is a prerequisite to dentinal caries and further damage to the tooth, the effectiveness of anticaries interventions can and should be evaluated, not only by its effect on cavitation, but also by its impact on non-cavitated lesion progression. Therefore, in future caries clinical trials, attempts should be made to incorporate appropriately standardized measurement systems to detect the effects of pre-cavitation demineralization and remineralization. Prevention of further demineralization and/or stimulation of remineralization in both non-cavitated and cavitated lesions, substantially beyond background noise, should therefore be sufficient to establish efficacy of an anticaries agent. The choice of caries measure(s) should be appropriate to the subject population, distribution of disease, and mechanism of action of the therapies studied. Site-specific determinations of mineral content and quality are not surrogate measures, but rather are primary indicators of the cumulative destructive impact of the caries process. It is an ongoing necessity to validate such measures for their power to discriminate between therapies relative to currently accepted observational methods. Clear and specific study aims are always essential to achieving a successful caries clinical trial. In addition, the use of ordinal or continuous measures of cumulative disease progression/regression, or rates of their occurrence when adequately standardized and precise, coupled with improved subject retention, offer26 INDIANA CONFERENCE 2005


the hope of increased efficiency in the conduct of clinical trials of anticaries therapies. Consensus Statements For confirmatory caries clinical trials, the statements below were the object of broad consensus by the assembled workshop participants: Study Objectives and Efficacy Variables (3.1) In conventional caries trials, the primary objective is to reduce DMFS increment; and the primary efficacy variable is, accordingly, reduction of DMFS increment (over a 2- to 3-year period). (3.2) In new caries trials, the study objectives should be directed at measuring changes in the continuum of the caries process. The efficacy variables should be a measure of further demineralization and/or stimulation of remineralization in lesions (substantially beyond what would naturally occur). (3.3) Measures of mineral density change are not surrogate outcomes, but rather are primary indicators of the cumulative status of the dental caries lesion. Surrogate variables are unacceptable as primary endpoints in caries clinical trials. Target/Sample Population (3.4) As is the case in all disease-focused clinical trials, caries studies need to identify subjects who are at high caries risk for inclusion in the study. This may mean, for example, that there will be age restrictions in the studys inclusion criteria. (3.5) Within the context set by the above criteria, caries studies should attempt to have broad representation with respect to gender, race, and socio-economic status. These inclusions are to promote generalizability to the target population. Study Designs (3.6) The randomized, maximally blinded parallel group design is the preferred study design for caries trials. (3.7) As in other areas of health sciences, multi-center caries trials may be necessary to achieve sample size goals or they may contributeCLINICAL MODELS WORKSHOP: REMIN-DEMIN, PRECAVITATION, CARIES 27

PITTS

certain other advantages in some circumstances. (3.8) Factorial designs can permit the possibility of investigating multiple therapeutic objectives. (3.9) All studies should be adequately sized and powered (conventionally, 0.05 level of significance and power at least equal to 0.80). This should be the case for superiority, non-inferiority, and equivalence trials. (3.10) In non-inferiority trials, the demonstration of compliance and adherence to protocols, a definition of non-inferiority margin, and a rigorous attempt to demonstrate that the active control was effective, are essential. Randomization (3.11) The randomization process should be clearly stated and documented. Blinding/masking should be maximal to the extent possible, considering the constraints inherent in trial design and the therapies to be used. Trial Monitoring (3.12) The use of an Ethics Committee/Institutional Review Board (IRB) is essential. In addition, a Data Safety Monitoring Board (DSMB) may be required for monitoring safety and efficacy. OBJECTIVE 4: Critically Review the Statistical Approaches That Could be Used to Analyze Modern Caries Clinical Trial Data Context The data generated by caries clinical trials present numerous challenges during the statistical analysis phase. The detailed measuring of the caries status at each specific tooth surface provides extensive and potentially rich information on each study participant. That information traditionally has been compressed during statistical analysis into a single outcome data point. The evolution of statistical methods that can capitalize on correlated intra-subject data has significantly broadened opportunities for the application of modern, powerful statistical methods that offer the prospect of more efficient analyses for caries trials. The participants in caries trials generally are healthy volunteers rather than patients. The healthy volunteer has less at stake in the study intervention than has28 INDIANA CONFERENCE 2005


the ill patient, often creating higher participant attrition in caries trials. On the other hand, caries-preventive treatments are generally benign and almost universally well accepted. Therefore, caries trial participants generally do not drop out due to effects linked to a poorly tolerated treatment regimen. Managing participant attrition and regimen compliance without incurring bias are important issues for data analysis of caries trials. Although caries trials have generally been analyzed by the treatment of caries increment as a continuous variable, validation studies of existing ordinally scaled clinical visual assessments should be conducted based on existing data from 2- to 3-year studies, comparing the results from ordinal scaling analyses with those from traditional caries increment analyses. Consensus Statements Following the presentation of all statistical methods papers, and the resultant plenary discussions, the Workshop participants elaborated on the following consensus statements relative to Objective 4. (4.1) The statistical analysis of a caries trial should utilize the maximum information available for the scale of measurement and the properties of the response variable (ordinal, counts, or continuous). (4.2) The statistical analysis should rely on robust techniques and be reported in a clinically interpretable manner. (4.3) Numerous statistical methodologies are available for analysis of the data from ordinal or continuous measures of change in mineralization. From among these, statistical methods should be chosen that appropriately reflect the experimental designs and efficiently capture the information produced. These include scoring of ordinal data, ordinal categorical data models, general and generalized linear models, and survival analysis methodology. (4.4) All methods should properly account for the possibility of intra-subject correlation. (4.5) For caries clinical trials, dichotomization of outcomes is often inefficient and should be avoided unless specifically justified by the declared goals of the trial. (4.6) The Intention-to-Treat (ITT) approach is problematic for extended caries trials, in view of the virtual unavoidability of extensive subject attrition, the typical loss of efficiency relative to analysisCLINICAL MODELS WORKSHOP: REMIN-DEMIN, PRECAVITATION, CARIES 29

PITTS

restricted to the subset of subjects who complete the full protocol (per protocol [PP] analysis), and the strong rationale and experiential basis for believing that dropouts occur randomly with respect to treatment. However, ITT analysis is generally recognized as the scientific standard for controlling bias and enhancing validity across the full range of medical clinical trials. (4.7) Modern statistical imputation methods may be useful in reducing the loss of efficiency from ITT relative to PP analyses and should be evaluated for their utility in caries trials. (4.8) To ensure that pivotal trials are sized adequately, the acceptability of primary PP analysis should be confirmed with regulatory authorities prior to data collection. (4.9) The appropriateness of a primary PP analysis should be explicitly justified in reports that take this approach, and a secondary ITT analysis should be provided. (4.10) In long-term caries trials reporting a primary ITT analysis, a secondary PP analysis may yield further understanding of the data. (4.11) It is essential that all trial participants are accounted for as part of the reporting process, as recommended by the CONSORT guidelines. (4.12) A considerable quantity of statistical literature exists on analytical methods when multiple outcomes are necessary to track a common underlying biological or target effect. Such methods include: (a) the use of a multivariate test statistic accounting for outcome variable correlation, or (b) appropriately standardized linear or non-linear combinations of outcomes to generate a composite variable or scale for analysis utilizing a global test statistic. (4.13) The magnitude of statistically significant treatment effects should be estimated and interpreted in clinical context. The interpretation of caries trials in terms of clinical significance requires further consideration OBJECTIVE 5: To ensure that, in meeting Objectives 1-4 (critically reviewing modern caries definitions and concepts, the evidence on cariesdiagnostic methods, potential designs for modern caries clinical trials, and the statistical approaches to analyze modern trial data), the Workshop for30 INDIANA CONFERENCE 2005


mulates key elements of protocol(s) for shorter and more efficient modern caries clinical trials and a framework for validating them endorsed by the group of leading international experts present at the meeting. Context The 4 sections above have, under the different objectives, already outlined several of the key elements that should be introduced into protocols for efficient, modern, caries clinical trials. In addition, there are several over-arching elements that were discussed and agreed on at the Workshop. These include the philosophy that clinical trials of anticaries agents should be considered within the same framework as clinical trials in other health care arenas. Hence, both the design and implementation of future caries trials should be considered in the full context of the modern science of clinical trial methodology, applied as appropriate to the special needs of oral health studies. Consensus Statements (5.1) In light of the evidence reviewed, both here and elsewhere pertaining to modern caries definitions and measurement concepts, the participants supported a statement recommending that, in future CCT protocols, caries measurement methods are to be used, which: are capable of accurately capturing, at any given point in time, the manifestations of the caries process in dental hard tissues (enamel and dentin); when applied sequentially, can monitor definitive changes in manifestations of the caries process over time, over and above any background noise from normal levels of de- and remineralization, or from variations attributable to the caries detection system(s) used; and when applied sequentially, can differentiate among actual product effects in terms of group differences in lesion initiation and lesion behaviour (progression, arrest, and/or regression). (5.2) If they are valid and contribute to the ability to improve trial efficiency, the new caries assessment technologies should be refined further and adopted in modern caries clinical trials.


31

PITTS

Validation of New Assessment Methods with Clinical Trials (5.3) Methods capable of recording the continuum of the caries process (including non-cavitated lesions) should be evaluated, and their results compared with those of conventional caries assessment methods over a 2- to 3-year study. (5.4) New caries assessment methods should have the ability to measure demineralization and remineralization of noncavitated lesions. (5.5) While there are many other ways in which the design of CCTs might be improved further, through better diagnostic, design, and analytical techniques, it is paramount that the overriding principle behind CCT design validation must be that the results and conclusions from any new design are in line with those shown previously by conventional CCTs. (5.6) Any new design of the caries clinical trial must not compromise the standard of proof of either efficacy or safety. Learnings From the ICW-CCT This meeting represented what participants claimed was an all too rare opportunity to hold an open, joint forum involving academic and commercial cariologists with input from industry, statisticians, and regulators. It employed an Evidence-Based approach, using systematic reviews of the literature, wherever possible, as well as incorporating much discussion and peer group synthesis. There will be a need for continuing activities to overcome inertia in this field and a push to implement new methods, which respond to new knowledge in the cariology field and which unlock the innovation needed to establish and test even more effective means of caries control. There is also a recognised need to ensure that any new standards or processes are updateable and to evolve as new data comes on stream from around the world. Following the ICW-CCT meeting, an unfunded ad hoc group of volunteers met to try to refine some of the tasks identified by the Workshop, which related to clinical visual examination, then to take this agenda forward. This initiative led to the formation of the initial ICDAS Committee in the spring of 2002. Overview Who participated? Ninety-five researchers from 23 countries, with representation from academia, industry, statistics, and regulatorsthis appears to32 INDIANA CONFERENCE 2005


have been the first comprehensive position review of caries clinical trials since 1968. What was the outcome? A unique multidisciplinary forum produced and agreed to detailed Consensus Statements, including the one that states that: For future clinical trials, recording cavitated lesions only as an outcome measure is becoming outmodedthe assessment of non-cavitated lesions is essential for future CCTs It is hoped that the ICW CCT proceedings and consensus statements will provide an increased understanding and guidance for the future conduct of caries clinical trials.

Acknowledgements The author is indebted to many individuals and organisations for contributing material presented in this paper. In particular, thanks are due to: John Stamm, a tireless co-chair and source of advice The Programme Committee, who chose extraordinarily well The Speakers, who all fulfilled their charge The Session chairs, who helped marshal the extended discussions The Delegates, who made the Consensus Statements coherent The Sponsors, who made the Workshop possible: - IADR, NIDCR, FDI - GlaxoSmithKline Inc., Procter & Gamble, Unilever, ColgatePalmolive Company, Sunstar, Gaba International Lion, and Wrigley This paper expresses the personal views of the author.

ReferencesFeatherstone JDB: The continuum of dental cariesevidence for a dynamic disease process. J Dent Res 2004;83 (Spec. Issue C): C39-C42. Horowitz AM: A report on the NIH Consensus Development Conference on Diagnosis and Management of Dental Caries Throughout Life. J Dent Res 2004;83 (Spec. Issue C): C15-C17. Ismail AI: Visual and visuo-tactile detection of dental caries. J Dent Res 2004;83 (Spec. Issue C): C56-C66.


33

PITTSKidd EAM, Fejerskov O: What constitutes dental caries? Histopathology of carious enamel and dentin related to the action of cariogenic biofilms. J Dent Res 2004;83 (Spec. Issue C): C35-C38. Longbottom C, Huysmans M-C DNJM: Electrical measurements for use in caries clinical trials. J Dent Res 2004;83 (Spec. Issue C): C76-C79. Pitts NB: Modern concepts of caries measurement. J Dent R 2004a;83 Spec. Issue C: 43-47. Pitts NB, Stamm J: ICW-CCT consensus statements. J Dent R 2004;83 Spec. Issue C: 125-128. Stookey G: Optical methodsQuantitative light fluorescence. J Dent Res 2004;83 Spec. Issue C: C84-C88.

34


ROC Analysis with Applications to Dental ResearchNancy A. Obuchowski Department of Quantitative Health Sciences The Cleveland Clinic Foundation Cleveland, OH, USA

Introduction Receiver Operating Characteristic (ROC) curve analysis has been used in many medical and non-medical fields to describe and compare the performance of predictors. For example, in diagnostic radiology, ROC curves are used to assess and compare imaging tests (the predictors) for diagnosing and screening for disease. ROC analysis is a powerful tool, and many statistical methods and software have been developed for it [Zhou et al., 2002; Pepe, 2003; ROC analysis software]. In this article, I discuss aspects of ROC curve analysis that are particularly relevant to dental research. Consider the following example,1 which I use throughout the paper to illustrate various ideas and statistical methods. Two hundred and twenty-seven sites on 83 exfoliated teeth from 35 patients were evaluated by each of 3 diagnostic methods (the predictors) for detecting caries [Katz Personal communication]. The 3 diagnostic methods were: 1) the DIAGNOdent reading, 2) delta_q, which is one of the measures generated by QLF, and 3) area, another measure generated by QLF. In this example, the study goal is to compare the 3 diagnostic methods to determine which is better at detecting caries. Thin sectioning was used to establish definitively whether or not caries was present. Such a procedure is called the gold standard or reference standard [Zhou et al., 2002; Weinstein et al., 2005]. For each site, a Plm result, scored on a 0-4 scale, was obtained. A Plm result of 1 or greater is considered as definitive for caries. Thus, the gold standard was used to establish between 2 truth states: caries absent vs. caries pres1

The data used in this example are a subset from a much larger study and, thus, are merely illustrative of the statistical methods described in this paper.


35

OBUCHOWSKI

ent (so-called binary-scale gold standard). We will also consider situations where the gold standard is on an ordinal-scale. In this discussion, we briefly address the situation when no gold standard data is available. In this example, multiple sites on the same tooth were tested, and multiple teeth from the same patient were included in the study sample. Multiple observations from the same patient are called clustered data. Observations from the same patient are often correlated, at least to some small degree. Ignoring this correlation leads to estimates of variance and standard errors that are artificially small, which can result in misleading conclusions. I will discuss methods for clustered ROC curve data. Finally, this example illustrates the comparison of 3 diagnostic tests performed, not on different samples of patients (unpaired or independent design), but rather on the same sample of patients (paired design). I will discuss a statistical test that takes advantage of this paired design. I conclude with a brief discussion of the 3 phases of assessment for evaluating diagnostic tests.

MATERIALS AND METHODS Describing a Diagnostic Tests Performance Sensitivity and Specificity There are 2 basic measures of the inherent accuracy of a diagnostic test: sensitivity and specificity. Sensitivity is the probability of a positive test result (e.g., the test indicates the presence of caries) for a site with caries. Specificity is the probability of a negative test result (e.g., the test does not indicate the presence of caries) for a site without caries. Table 1 illustrates the definitions of sensitivity and specificity. The rows of the table give the results of the diagnostic test as either positive for the presence of caries or negative for caries. The columns indicate the true caries status. True positives (TP) are those sites where the Plm result is positive for caries and the diagnostic test is positive for caries. True negatives (TN) are sites without caries that test negative. False negatives (FN) are those with caries, but the test falsely indicates that caries is not present. False positives (FP) are those without caries, but the test falsely indicates the presence of caries. Sensitivity, then, is the probability of a TP among sites with caries (TPs + FNs); i.e., sensitivity =36 INDIANA CONFERENCE 2005

ROC ANALYSIS WITH APPLICATIONS TO DENTAL RESEARCHCaries Present1 Test positive2 Test negative212

Caries Absent1 3 (FP) 175 (TN)

6 (TP) 43 (FN)

based on a Plm score 0 0 >0 >0 0 >0 0 >0 >0

DIAGNOdent 0 0 0 1 1 1 1 3 5 5 8 10 21 25 89

Sensitivity 1.0 1.0 1.0 0.714 0.714 0.714 0.714 0.714 0.429 0.429 0.429 0.286 0.286 0.143 0.0

Specificity 0.375 0.375 0.375 0.625 0.625 0.625 0.625 0.750 0.750 0.750 0.875 0.875 1.0 1.0 1.0

FPR 0.625 0.625 0.625 0.375 0.375 0.375 0.375 0.250 0.250 0.250 0.125 0.125 0.0 0.0 0.0

FPR = false positive rate, or 1- specificity

TABLE 3.

Diagnostic test data sorted by DIAGNOdent result.

without caries. The ROC area can also be interpreted as the average sensitivity for all FPRs, or the average FPR over all sensitivities [Metz, 1989]. The area under the ROC curve is calculated as follows: Let Xi denote the result of the diagnostic test (e.g., DIAGNOdent reading) for the i-th site with caries (as determined by the gold standard), and let Yj denote the result of the diagnostic test for the j-th site without caries. A nonparametric estimator of the area under the ROC curve, AUC, is: AUC = [D + 0.5 x E]/(m x n)


39

OBUCHOWSKI

where n is the number of sites with caries (as determined by the gold standard) and m is the number of sites without caries in the study sample. If one were to compare the diagnostic tests results of each of the nsites with caries to each of the m sites without caries, then there would be m x n such comparisons. D is the number of these comparisons, where the site with caries has a higher (more suspicious) score on the diagnostic test than the site without caries; E is the number of comparisons, where the 2 sites have the same score on the diagnostic test. Table 4 illustrates the calculation of the ROC area for the 15 observations given in table 2. In the next 2 sections, I will discuss methods for formally testing the null hypothesis that 2 diagnostic tests have the same accuracy versus the alternative hypothesis th

7th proceedings indiana conference

Documents

oral research

caries george

dental research nancy

national institute of

dental caries hannu

oral presentations

pivotal clinical trials

r43 de016767